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The aim of the present study was to explore the dynamic relationship between Notch and non-alcoholic fatty liver disease (NAFLD), both in vitro and in vivo. The LX2, Huh7 and MIHA hepatic cell lines were used to establish a cell steatosis model induced by palmitic acid (PA) at different concentrations (0.1, 0.25 and 0.5 mM). Cell proliferation and migration were assessed using a 5-bromo-2′-deoxyuridine kit and a wound healing assay. The dosage of 0.25 mM PA for 36–48 h treatment was chosen for subsequent experiments. Steatotic cells were identified by Oil Red O staining. Feeding mice a methionine-choline-deficient (MCD) diet is known induce a model of NAFLD, compared with a methionine-choline-sufficient (MCS) diet. Therefore, Notch family mRNA expression was evaluated in the liver of MCD-fed mice at varying time points (days 5, 10, 21 and 70) using reverse transcription-quantitative PCR. Notch expression levels were also assessed in cell lines at 12, 24, 36 and 48 h after PA treatment. Notch signaling molecules changed in the PA or MCD model over time. In vitro, the mRNA levels of Notch1, −2 and −4 increased in all cell lines after 12-h PA treatment. At 24 h, these genes were upregulated only in LX2 cells, while showing a ‘down-up’ pattern in MIHA cells (i.e. these genes were downregulated at 24 h but upregulated at 36 h). However, expression of Notch1, −2, −3 and −4 mRNA rose significantly in the early stage (day 10) of NAFLD. At week 3, the levels of Notch1 and −2 were higher in the MCD group than in the MCS group, while the reverse was observed for Notch3 and −4. Expression of these four genes increased again in the late stage (day 70) of NAFLD. Therefore, these results indicated that Notch family members Notch1-4 were involved in the development of NAFLD and played an important role in steatosis in this model.

Aims Prolyl endopeptidase (PREP) is a serine endopeptidase widely distributed in the body, and accumulated evidence suggests that PREP participates in inflammation and oxidative stress. Here, we explored the effect of PREP gene disruption on hepatic inflammation and oxidative stress status in a methionine-choline-deficient (MCD)-induced nonalcoholic steatohepatitis (NASH) model. Main methods PREP gene disruption (PREPgt) mice and wild-type (WT) littermates were placed on a control or an MCD diet for 4 weeks, respectively. The liver histopathological analysis and the number of inflammatory cells were determined by hematoxylin-eosin (HE) and immunohistochemical staining. Inflammation-associated genes and cytokine levels in liver tissue were evaluated by quantitative PCR and ELISA. The levels of P53, Sesn2, Nrf2, HO-1, and oxidative stress indicators in mice and the palmitic acid (PA)-treated human hepatocellular carcinoma cells (HepG2) were examined by immunoblotting and commercially available kits, respectively. Key findings We found that PREP expression was upregulated in the MCD-induced NASH model. In addition, PREP disruption alleviated MCD-induced hepatic inflammation accompanied by diminished infiltration of inflammatory cells and secretion of inflammatory mediators. More importantly, the results of this study indicate that targeting PREP can improve oxidative stress status in the liver of MCD-diet mice and PA-exposed HepG2 cells. The effect is most likely mediated by the activation of P53 and its downstream signaling pathways (Sesn2/Nrf2/HO-1). Significance Our results showed that PREP disruption (or inhibition) could decrease oxidative stress and inflammation and improve liver function, indicating that targeting PREP might be a new potential therapeutic option for NAFLD/NASH.

Non-alcoholic steatohepatitis (NASH) is an epidemic metabolic disease with limited therapeutic strategies. Cumulative data support the pivotal role of gut microbiota in NASH. Here, we investigated the hypothesis regarding whether fecal microbiota transplantation (FMT) is effective in attenuating high-fat diet (HFD)-induced steatohepatitis in mice. Mice were randomized into control, HFD and HFD + FMT groups. After an 8-week HFD, FMT treatment was initiated and carried out for 8 weeks. The gut microbiota structure, butyrate concentrations of the cecal content, liver pathology and intrahepatic lipid and cytokines were examined. Our results showed that after FMT, the gut microbiota disturbance was corrected in HFD-fed mice with elevated abundances of the beneficial bacteria Christensenellaceae and Lactobacillus. FMT also increased butyrate concentrations of the cecal content and the intestinal tight junction protein ZO-1, resulting in relief of endotoxima in HFD-fed mice. Steatohepatitis was alleviated after FMT, as indicated by a significant decrease in intrahepatic lipid accumulation (reduced Oli-red staining, decreased intrahepatic triglyceride and cholesterol), intrahepatic pro-inflammatory cytokines, and the NAS score. Accordingly, intrahepatic IFN-γ and IL-17 were decreased, but Foxp3, IL-4 and IL-22 were increased after FMT intervention. These data indicate that FMT attenuated HFD-induced steatohepatitis in mice via a beneficial effect on the gut microbiota.

Background: Endothelial cells have been shown to be in response to a variety of local and systemic stimuli, and are able to transition between quiescent and activated states. Endothelial cell activation is critical for the pathogenesis of various cardiovascular diseases. However, the expression changes of long non-coding RNAs (lncRNAs) are still unknown in the process of endothelial cell activation. Thus, this study was aimed to investigate expression changes of lncRNA before and after endothelial cell activation. Materials and Methods: In an experimental model of peripheral venous congestion, endothelial cells were activated and analyzed with Affymetrix HG-U133 plus2.0 microarray. We analyzed these microarray data and reannotated the microarray probes for lncRNA. Results: According to the definition of absolute fold change>2 and p value

The homeobox B8 (HOXB8) functions as a sequence-specific transcription factor that is involved in development. Increased expression of this gene is associated with a wide variety of tumor; however, its function in gastric cancer has not been clarified. In the present study, the expression of HOXB8 in gastric cancer tissues and influence of HOXB8 on gastric cancer cellular were evaluated. The expression levels of HOXB8 mRNA in human gastric cancer tissues were analyzed through quantitative RT-PCR. To test the role of HOXB8 in gastric cancer metastasis, the cell transwell assay was performed. Microarray, ChIP-qPCR, and Western blot were used to explore the possible mechanism that HOXB8 promotes gastric cancer cells metastasis. In this study, we found that HOXB8 showed higher expression in metastatic tissues than no-metastatic tissues. Overexpression of HOXB8 can promote gastric cancer cells migration and invasion, while silencing HOXB8 leads to the opposite results. Overexpression of HOXB8 also increases the rate of metastasis in NCI-N87 mice, while silencing HOXB8 has the opposite results. Furthermore, HOXB8 promotes epithelial–mesenchymal transformation of AGS cells. We also found that ZEB2 can interact with HOXB8 and may be a downstream factor of HOXB8 by using microarray. Knockdown of ZEB2 can inhibit HOXB8-induced migration and invasion capacity, as well as the epithelial–mesenchymal transformation in gastric cancer cells. The results showed that HOXB8 plays an important role in the development and metastasis of gastric carcinoma.

BACKGROUND: To investigate Kip1 ubiquitination-promoting complex 1 (KPC1) expression and its relationship with NF-κB p50 in gastric cancer cell lines. METHODS: The expression of KPC1 and NF-κB p50 in tissue samples from 159 gastric cancer patients after tumor resection and normal gastric mucosa samples from 56 patients as negative controls was retrospectively studied. The relationship between KPC1, NF-κB p50, and clinicopathological factors was analyzed, and the correlation between KPC1 and cytoplasmic NF-κB p50 was determined. The expression level of KPC1 and NF-κB p50 was researched using reverse transcription (RT) polymerase chain reaction (RT-PCR) and Western blotting in 3 differentiated human gastric cancer cell lines (AGS, SGC-7901 and MGC-803). RESULTS: Immunohistochemistry indicated that KPC1 and NF-κB p50 expression was significantly decreased in gastric cancer cases, and the level of expression varied across the differentiated gastric cancer tissues. KPC1 and NF-κB p50 expression was significantly connected with tumor differentiation, tumor-node-metastasis (TNM) staging, and metastasis of 159 patients suffering from gastric cancer (P0.05). KPC1 was positively connected with the expression of NF-κB p50 by the Spearman correlation analysis (r=0.427, P

Radiation therapy is one of the most important methods for the treatment of malignant tumors. However, in radiotherapy for thoracic tumors such as breast cancer, lung cancer, esophageal cancer, and mediastinal lymphoma, the heart, located in the mediastinum, is inevitably affected by the irradiation, leading to pericardial disease, myocardial fibrosis, coronary artery disease, valvular lesions, and cardiac conduction system injury, which are considered radiation-induced heart diseases. Delayed cardiac injury especially myocardial fibrosis is more prominent, and its incidence is as high as 20–80%. Myocardial fibrosis is the final stage of radiation-induced heart diseases, and it increases the stiffness of the myocardium and decreases myocardial systolic and diastolic function, resulting in myocardial electrical physiological disorder, arrhythmia, incomplete heart function, or even sudden death. This article reviews the pathogenesis and prevention of radiation-induced myocardial fibrosis for providing references for the prevention and treatment of radiation-induced myocardial fibrosis.

Gut microbiota plays a significant role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study aimed to assess the contribution of gut microbiota dysbiosis to the pathogenesis of NAFLD.Forty-seven human feces samples (25 NAFLD patients and 22 healthy subjects) were collected and 16S rDNA amplicon sequencing was conducted on Hiseq 2000 platform. Discrepancy of species composition between controls and NAFLD group was defined by Metastats analysis under P value0.01.NAFLD patients harbored lower gut microbiota diversity than healthy subjects did. In comparison to the control group, the Proteobacteria (13.50%) and Fusobacteria (2.76%) phyla were more abundant in NAFLD patients. Additionally, the Lachnospiraceae (21.90%), Enterobacteriaceae (12.02%), Erysipelotrichaceae (3.83%), and Streptococcaceae (1.39%) families, as well as the Escherichia_Shigella (10.84%), Lachnospiraceae_Incertae_Sedis (7.79%), and Blautia (4.95%) genera were enriched in the NAFLD group. However, there was a lower abundance of Prevotella in the NAFLD group than that in the control group (5.83% vs 27.56%, P0.01). The phylum Bacteroidetes (44.63%) also tended to be more abundant in healthy subjects, and the families Prevotellaceae (28.66%) and Ruminococcaceae (26.44%) followed the same trend. Compared to those without non-alcoholic steatohepatitis (NASH), patients with NASH had higher abundance of genus Blautia (5.82% vs 2.25%; P=0.01) and the corresponding Lachnospiraceae family (24.33% vs 14.21%; P0.01). Patients with significant fibrosis had a higher abundance of genus Escherichia_Shigella (12.53% vs 1.97%; P0.01) and the corresponding Enterobacteriaceae family (13.92% vs 2.07%; P0.01) compared to those with F0/F1 fibrosis.NAFLD patients and healthy subjects harbor varying gut microbiota. In contrast to the results of previous research on children, decreased levels of Prevotella might be detrimental for adults with NAFLD. The increased level of the genus Blautia, the family Lachnospiraceae, the genus Escherichia_Shigella, and the family Enterobacteriaceae may be a primary contributor to NAFLD progression.

By utilizing chrysotile asbestos tailing from Shannan ore in Sichuan as the main raw material, diopside-based glass-ceramics were successfully synthesized in the laboratory by adding some limestone, quartz sand, Al2O3, H3BO3, Na2CO3 and CaF2. The optimum procedure for glass-ceramics was as follows: melting at 1400 for 60 min, sintering at 1100 for 120 min. Through the tests of physical and mechanical properties, the glass-ceramics materials with more crystalline phase had high density, fine performance of resisting compression (366MPa) and negligible water absorption. Through chemical resistance tests, the glass-ceramics samples showed strong corrosion resistance. Overall result indicated that it was a feasible attempt to produce glass-ceramics materials for building and decorative materials from chrysotile asbestos tailing.

Associations between thyroid function and non-alcoholic fatty liver disease (NAFLD) are unknown in chronic hepatitis B (CHB)-infected patients. Thus, the aim of the study was to investigate the prevalence of thyroid dysfunction and its relationship with NAFLD in CHB.Consecutive naive CHB infected patients that had undergone liver biopsy and serum thyroid function tests between January 2007 and December 2011 were retrospective analyzed. NAFLD was diagnosed as at least 5% biopsy-proven hepatic steatosis without significant alcohol consumption.A total of 1154 non-alcoholics with CHB were included, 270 (23.39%) patients were found to have NAFLD, most of them (88.5%) with mild steatosis. The prevalence of hyperthyroidism and hypothyroidism (including subclinical and overt) was 1.56% and 1.64%, respectively, both with similar rates in patients with and without NAFLD (1.85% vs 1.47%, 1.48% vs 1.69%, respectively, both P 0.05). The serum thyroid-stimulating hormone (TSH) level in NAFLD patients was significantly higher than that in patients without NAFLD (2.22 ± 2.13 vs 1.61 ± 1.20 mIU/L, P 0.05). After adjustment for age and gender, the elevated TSH level was associated with increased odds of having steatosis (odds ratio1.54, 95% confidence interval 1.049-2.271) instead of viral factors and hepatic inflammation and fibrosis.Thyroid dysfunction is not common in CHB-infected patients, and the prevalence of hypothyroidism in CHB individuals with or without NAFLD is similar. However, increased serum TSH concentration at the normal range is a significant predictor of hepatic steatosis in patients with CHB.

Background Nonalcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC), but the association between a high-fat diet (HFD) and HCC is not fully understood. In this study, we investigated whether a high-saturate-fat diet affects hepatocarcinogenesis induced by administration of diethylnitrosamine (DEN). Methods Adult SD rats were randomized into the following groups: normal chow diet (NCD), HFD, NCD + DEN, and HFD + DEN. The HFD contains 2% cholesterol and 10% lard oil. In mice with DEN treatment, the carcinogen was given via gavage. Mice were sacrificed at the end of 10, 12, and 14 weeks, respectively. The effects of HFD on hepatic carcinogenesis were assessed by HCC incidence, tumor differentiation, and the number and size of tumor nodules. Western blot and immunohistochemistry for proliferating cell nuclear antigen (PCNA), enzyme-linked immunosorbent assay (ELISA) for caspase-3, and real-time PCR for TNF-α and IL-6 further uncovered the proliferative and apoptotic properties of liver. Results In contrast to the NCD group, DEN treatment (NCD + DEN group) led to hepatitis, cirrhosis, hepatic tumor, and decreased body weight. Interestingly, HFD, which induced hyperlipidemia and hepatic steatosis, attenuated DEN-related malnutrition and fibrosis progression in HFD + DEN group during 10–14 weeks. Moreover, the HFD + DEN group exhibited that the proportion of well differentiated HCC was much higher than that of NCD + DEN group. The number and average volume of HCC node were also significantly lowered in HFD + DEN group (P

Recent evidence has indicated that polyunsaturated fatty acids (PUFA), such as omega-3 PUFA, have protective effects on a range of chronic inflammatory conditions, including obesity, and may play a role in the reversal of steatohepatitis. However, the effects of omega-3 PUFA on adipokine expression and hepatic lipid metabolism have not been well evaluated. Thus, the aim of our study was to investigate the effects of PUFAs on adipokines, as well as lipid and glycometabolism, in a rat model of non-alcoholic steatohepatitis (NASH).Male Sprague-Dawley rats were divided into control, model and therapy groups. The control group received a normal diet, while the model and therapy groups received a high-fat diet. On the eighth week of high-fat diet, the therapy group was treated with omega-3 PUFA (1.0 g/d) daily. At the end of 20 weeks, serum biochemistry indices were measured and adipokine levels in serum and liver samples were detected with ELISA, Western blotting and real time fluorescence quantitative PCR (qRT-PCR).The weight, biochemical parameters and adipokine levels in serum of the model group were elevated compared to the control group (P0.05). In addition, the protein and mRNA expression levels of adipokines in the liver were significantly altered compared to the control group (P0.01). The therapy group was characterized by decreased weight and biochemical indices (P0.05) compared with the model group. Supplementing high-fat diet with omega-3 PUFA decreased serum levels of leptin and resistin, while adiponectin levels were slightly elevated. In liver tissue samples, the protein and mRNA expression levels of adipokines were significantly improved (P0.01) in the therapy group compared to the model group.Omega-3 PUFA improved lipid and glycometabolism in NASH rats and regulated adipokine expression, indicating that omega-3 PUFA may have a therapeutic benefit for patients with NASH.

This study investigates the varied expression of DNA methyltransferase (DNMT) proteins in gastric cancer (GC) and their relationship with the biological behavior of the tissues. Immunohistochemistry was used to detect the expression of the 3 DNMTs in gastric tissues. We discovered that the positive rates of DNMT1, DNMT3a, and DNMT3b expression in GC tissues were 81.6%, 81.6%, and 68.4%, respectively, and they were significantly higher than those of both para-cancerous (39.5%, 50%, and 44.7%) and normal tissues (10.5%, 10.5%, and 7.9%). DNMT1 was well distributed in the cytoplasm and nuclei of tumor cells or glands, while DNMT3a and 3b were well distributed only in the cytoplasm, as shown by staining a dark brown color. A significant correlation between the DNMT1 and DNMT3a proteins (P0.01), a low correlation between DNMT3a and DNMT3b (P0.05), and no correlation between DNMT1 and DNMT3b (P0.05) were observed. DNMT1 protein expression exhibited no correlation with age, lymphnode metastasis, and also tumor differentiation, but it may have had a correlation with gender. The DNMT3 family was not associated with these factors. Therefore, DNMT overexpression is involved in gastric tumorigenesis, but there is no correlation between the DNMTs and the biological behaviors of tissues.